Dibenzocycloheptenes

ABSTRACT

10-(1-AMINOALKYL)-10,11-DIHYDRO - 5H - DIBENZO(A,D) CYCLOHEPTENES, E.G. THOSE OF THE FORMULA   5-(X=),10-R3,10-(AM-ALK-),R1,R2-10,11-DIHYDRO-5H-DIBENZO-   (A,D)CYCLOHEPTENE   AN=AN AMINO GROUP ALK=LOWER ALKYLIDENE X=2H, HOH OR O R1,2=H, ALKYL, ALKOXY, ALKYLMERCAPTO, HALO, CF3, NO2 OR AMINO R3=H, LOWER ALKYL AND SALTS THEREOF ARE ANTIDEPRESANTS.

States Patent @ffi-ce 3,812,119 Patented May 21, 1974 3,812,119 DIBENZOCYCLOHEPTENESI Gordon Northrop Walker, Morristown, NJ, assignor to Ciba-Geigy Corporation, Ardsley, N.Y. No Drawing. Continuation-impart of abandoned application Ser. No. 878,914, Nov. 21, 1969. This application Aug. 28, 1970, Ser. No. 68,037 I Int. Cl. C07d 87/40 U.S. Cl. 260-247 5 Claims ABSTRACT OF THE DISCLOSURE v-(1 aminoalkyl)-l0,ll-dihydro 5H dibenzo[a,d] cycloheptenes, e.g. those of the formula elk-Am Arn=an amino group alk=lower alkylidene X=2H, HOH or O R =H, alkyl, alkoxy, alkylmercapto, halo, CF N0 1 or amino Rg=H, lower alkyl and salts thereof are antidepressants.

CROSS-REFERENCES To RELATED APPLICATIONS This is a continuation-in-part of application Serial No. 878,914, filed Nov. 21, 1969, now abandoned.

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new 10-(1-aminoalkyl)-l0,ll-dihydro- SH-dibenzo[a,d]cycloheptenes, preferably of those corresponding to Formula I II X DESCRIPTION OF THE PREFERRED EMBODIMENT The 1,2-phenylene radicals Ph, and Pb; are unsubstituted or substituted in the remaining 4 positions by one or more than one, preferably by one or two, of the same or different substituents, for example, lower alkyl, e.g. methyl, ethyl, nor i-propyl or -butyl; etherified or esterifled hydroxy or mercapto, such as lower alkoxy or alkylmercapto, e.g. methoxy, ethoxy, nor i-propoxy or -butoxy, methylmercapto or ethylmercapto, halo, e.g. fluoro, chloro or bromo; trifluoromethyl; nitro; amino or di-lower alkylamino, e.g. dimethylamino or diethylamino. The term lower, referred to above and hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, carbon atoms.

Preferred radicals Ph, and Ph are above all 1,2- phenylene, but also (lower alkyl)-1,2-phenylene, (lower alkoxy) -l,2-phenylene, (halo)-1,2-phenylene, (trifiuoromethyl)-1,2-phenylene, (nitro)-l,2-phenylene or (amino)- 1,2-phenylene.

The radical R is preferably hydrogen, but also lower alkyl, such as ethyl, nor i-propyl or butyl, or above all methyl. The lower l-alkylene radical alk is preferably methylene, but also l-ethylene, 1- or 2-propylene or -butylene.

The amino group Am is preferably a tertiary amino group containing advantageously one or two radicals of aliphatic or one of aromatic character. Such amino groups are, for example, lower alkyleneimino or alkenyleneimino, e.g. ethyleneimino, pyrrolidino, pyrrolino, piperidino, 4-phenylpiperidino, 1,4-pentyleneimino, 2,5- or 1,6-hexyleneimino, or 1,7- or 2,6-heptyleneimino, 2-aza- 2-bicyclo[2,2,1]heptyl, 2-aza-2-bicyclo[2,2,2] or [3,2,1] octyl, 3-aza-3-bicyclo[3,2,l] or [3,3,0]octyl, 2-aza-2- bicyclo[3,2,2] or [3,3,1]nonyl, 3-aza-3-bicyclo[3,2,2] or [3,3,1]nonyl, 2-aza-2-, 3-aza-3-, 7-aza-7- or 8-aza-8- bicyclo[4,3,0]nonyl or 2-aza-2- or 3-aza-3-bicyclo[4,4,0] decyl, or monocyclic monoaza-, oxaor -thia-lower alkyleneimino or N-(lower alkyl, hydroxylower alkyl, HPh -lower alkyl or HPhQ-rnonoaza-lower alkyleneimino, wherein heteroatoms are separated from each other by at least 2 carbon atoms, e.g. piperazino, 4- (methyl, ethyl, 2-hydroxyethyl, benzyl or phenyl)-piperazino, 3-aza-l,6-hexyleneimino, 3- (methyl or ethyl) -3- aza-1,6-hexyleneimino, 4-aza-1,7-heptyleneimino or 4- (mthyl or ethyl)-4-aza-1,7-heptyleneimino, morpholino, 3,5-dimethylmorpholino or thiamorpholino.

The compounds of the invention exhibit valuable pharmacological properties, for example, antidepressant or amphetamine potentiating effects. This can be demonstrated in animal tests, using advantageously mammals, such as mice, rats, or monkeys as test animals. The compounds of the invention can be applied to the animals orally, preferably subcutaneously or intraperitoneally, e.g.

in the form of aqueous solutions or suspensions. The dos-.

age may range between about 1 and 500 mg./kg./day, preferably between about 5 and mg./-kg./ day, advantageously between about 10 and 25 mg./kg./day. A depressant effect is recorded in the mouse jiggle cage test system, where the spontaneous movements of the animals are registered, or an antidepressant effect in the amphetamine test, which is performed as disclosed by P Carlton, Psychopharacologia, 1961, vol. II, p. 364. In accordance with the above procedure, about 8 month old male rats are trained to press a bar every 30 seconds, in order to avoid an electric shock applied through the floor grid. In the case where the animals receive 0.25 mg./kg./day of amphetamine, their performing rate for avoiding said shocks during a test period of about 2% hours is higher than that of placebo (saline) treated animals. In the case where the animals receive the compounds of the invention in the above-mentioned doses and about 45 minutes later the amphetamine, their rate of avoidance is highest, as compared with that of animals receiving (a) saline alone, (b) saline and amphetamine or (c) the compounds pounds of the invention are useful antidepressants in the treatment or management of exoor endogenous depres- R: CI-Ir-Am in which each of R and R is hydrogen, methyl, methoxy, chloro, trifluoromethyl, nitro or amino, R is hydrogen or methyl, Am is pyrrolidino, piperidino, 4-phenylpiperidino, hexamethyleneimino, piperazino, morpholino or 4- (methyl, ethyl or 2-hydroxyethyl)-piperazino and X represents two hydrogen atoms, or therapeutically acceptable acid addition salts thereof.

Outstanding are compounds of Formula II, in which each of R R and R3 is hydrogen, Am is pyrrolidino, piperidino, 4-phenylpiperidino, piperazino, morpholino or 4-(methyl, ethyl or 2-hydroxyethyl)-piperazino and X is two hydrogen atoms, or therapeutically acceptable acid addition salts thereof.

The compounds of the invention are prepared according to methods known per se. For example, they are obtained by:

(a) Converting in a compound of Formula III Ph Phi ii in which Y is a substituent capable of being converted into alk-Am, Y into said aminoalkylidene group, or

(b) Opening in a compound of Formula IV in which Z is a group capable of being converted into Am by hydrogenolysis of the Z-CH bond, Z into Am, or

(c) Wherein R is hydrogen, hydrogenating in a compound of Formula V the 10,11-double bond and, if desired, converting any re- V lithium aluminum hydride.

trolytically or by the action of metals on compounds with active hydrogen, such as acids or alcohols, e.g. zinc or iron and inorganic or organic acids, such as hydrohalic or lower alkanoic acids, or sodium or aluminum or their amalgams and lower alkanols. i v v v The ring-opening or hydrogenation processes mentioned under items (b) and (c) are similarly performed as the above-described reduction steps, preferably with the use sulting compound into another compound of the invention. The substituent Y is, for example, a reactively esterilower alkane or benzene sulfonic acid, e.g. methane, ethane, benzene or p-toluene sulfonic acid, or a phosphoniumalkylidene group, e.g. a triphenyl-phosphonium halidealkylidene group. Said groups Y are converted into alk- Am by condensation with H-Am or an alkali metal, e.g.

sodium salt thereof.

Another substituent Y is, for example, a (nitro, oximino or imino) -alkylidene group or preferably a cyano or carbamoyl group, e.g. CO-Am, which groups can be converted into alk-Am by reduction. The above nitro compounds,

nitriles or amides are advantageously reduced with the. I

use of simple or complex light metal hydrides, such as boron hydride or alkali metal aluminum hy of catalytically activated hydrogen.

The compounds of the invention so obtained can be converted into each other according to methods known per se. For example, resulting primary, secondary or tertiary amines can be reacted with reactive esters of corresponding alcohols or with corresponding aldchydes or ketones and reducing agents, e.g. formic acid, its functional derivatives or nascent hydrogen, in order to obtain secondary or tertiary amines, or quaternaries respectively.

' Resulting primary or secondary amines or S-hydroxy compounds, can also be acylated, for example, with the use of the corresponding acid halides or anhydrides, or acyl derivatives obtained hydrolyzed, e.g. with acids or alkalies, or reduced with simple or complex light metal hydrides. Resulting tertiary amines can be converted into N-oxides or secondary amines, for example by treating them with oxidation or acylating agents, such as hydrogen peroxide or peracids, or acid halides or anhydrides,

respectively, e.g. aliphatic or aromatic percarboxylic acids,

or haloformic acid esters. Furthermore, nitro groups may be introduced into aromatic moieties, e.g. by the action of nitric-sulfuric acid or by pyrolysis of nitrates, advantageously in acidic media, e.g. intrifiuoroacetic acid, or nitro groups present therein reduced, e.g. with nascent hydrogen. A resulting S-oxo compound can likewise be reduced to the corresponding S-hydroxy or S-unsubstituted compound, for example, with the aid of the respective ketone reducing agents, such as complex light metal hydrides, e.g. those mentioned above, metallic alkoxides,

e.g. aluminum alkoxides according to MeerWein-Ponn dorf-Verley, or catalytically activated or nascent hydrogen. Resulting S-hydroxy compounds may also be oxidized to the corresponding S-ketones with the usual alcohol dehydrogenation (oxidation) agents, such as oxygen in the presence of catalysts, e.g. silver, maganese, iron or cobalt catalysts, oxidation agents, such as oxidizing acids or their salts, e.g. hypohalous, periodic, nitric or chromic acid or suitable salts thereof, e.g. sodium hypochlorite, potassium dichromate or permanganate, heavy metal salts or oxides, e.g. chromic, cupric or ferric halides or sulfates or silver, mercuric, vanadium V,"chromium VI or manganese IV oxide, in acidic or alkaline media, or according to Oppenauer with the use of metallic alkoxides and simple ketones, e.g. acetone or cyclohexanone. Finally, a resulting basic compound can be converted into a corresponding acid addition salt, for example by reacting it with an inorganic or organic acid, such as a therapeutically use-- ful acid, or with a corresponding anion exchange preparation, and isolating the desired salt. A resulting acid addition salt may be converted into the free compound by treatment with a base, e.g. a metal hydroxide, ammonia or a hydroxyl ion exchange preparation. Therapeutically useful acids are, for example, inorganic or organic acids, such as strong metalloidic acids, for example, a hydrohalic, e.g.

hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid, or aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic,-succinic, glycollic, lactic, malic, tartaric, citric, ascorbic,

maleic, hydroxymaleic, pyroracemic, phenylacetic, ben-' zoic, 4aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic,

halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; methionine, tryptophan, lysine or arginine.

These or other salts, for example; the picrates, can also be used for purification of the resulting free compounds, which are converted into salts, the salts separated and the free compounds liberated from the salt. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

Resulting mixtures of isomers can be separated into the single isomers by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, e.g. by the fractional crystallization of dor l-tartrates.

The above reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing, neutralizing agents and/ or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure.

The invention also comprises any modification of the above process, wherein a compound resulting as an intermediate at any stage thereof, is used as starting material and the remaining steps are carried out or the process is discontinued at any stage thereof, or in which the starting material is formed under the reaction conditions or is used in the form of its salts or reactive derivatives. Those starting materials are preferably used, which lead to those compounds of the invention, which are indicated above as the preferred embodiments of the invention.

The starting material used is known or, if new, may be prepared according to methods known per se. For example, the starting material mentioned under item (a) is prepared by ring-closure of compounds of the formula in which one of R and R is hydrogen and the other free or reactively converted carboxy, e.g. chlorocarbonyl, according to the Friedel-Crafts reaction, i.e. the presence of Lewis acids, e.g. polyphosphoric acid or aluminum chloride. Furthermore, when R is alkyl, said radical can be introduced by alkylation of the above ring-closed compounds, for example, with a reactive ester of a lower alkanol, R-OH, such as a lower alkyl halide, e.g. methyl iodide, in the presence of a base, such as a metal hydride, alkoxides or hydroxide, e.g..sodium methoxide, ethoxide, hydroxide or especially sodium hydride. The compounds mentioned under item (b) can be obtained by reducing compounds of Formula III, wherein X is oxo and Y is carboxy, with sodium-borohydride, converting the resulting cyclic lactone into that of the corresponding hydroxamic acid with the use of hydroxylamine, hydro genating the resulting compound with catalytically activated hydrogen to form the cyclic lactam, if desired reacting it, or its alkali metal salt, with a reactively esteridied aliphatic, or cycloaliphatic araliphatic alcohol and reducing the N -Hnsubstituted or substituted lactame with a complex light metal hydride, e.g. lithium aluminum hydride. Finally, the compounds mentioned under item (c) can be prepared according to Netherlands application 6611324 (Chem. Abstr., 1967, 90587).

The pharmacologically active compounds of the inven tion are useful in the manufacture of pharmaceutical compositions containing an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose,=dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylenegly'col, for tablets also (0) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinyl-pyrrolidone, if desired, (d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes, of the binders or efiervescent mixtures and/or (e) adsorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Said pharmaceutical compositions may also contain other therapeutically valuable substances. They are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 The mixture of 3 g. 5-oxo-l0-cyano-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene, 200 ml. ethyl acetate and 2 g. 10% palladium on charcoal is hydrogenated at 60 under an initial pressure of 3 at. for 3 hours. It is filtered, the filtrate evaporated in vacuo, the residue taken up in diethyl ether, the solution extracted with 5% hydrochloric acid, the extract made basic with aqueous sodium hydroxide and the mixture extracted with diethyl ether. The extract is washed with water, dried and evaporated, the residue taken up in ethanol, the solution acidified with ethanolic hydrochloric acid and the precipitate formed recrystallized from ethanol, to yield the 5-oxo-l0-aminomethyl-10,11-dihydro-5H dibenzo[a,d]cycloheptene hydrochloride of the formula melting at 264-266.

The starting material is prepared as follows: To the solution, prepared from 12.6 g. sodium and 400 ml. methanol, 64.5 g. phenylacetonitrile are added while stirring, followed by 50 ml. methanol. After 20 minutes 75 g. phthalaldehydic acid are added and the mixture refluxed for v2 hour. It is acidified with N-hydrochloric acid while chilled with ice and the whole poured into ice water. The precipitate formed is filtered off, washed with water, dried and recrystallized from ethyl acetate, to yield the ct (2 carboxybenzylidene)-phenylacetonitrile melting at 178-180".

The mixture of 11.1 g. thereof, 300 ml. ethyl acetate and 4 g. 10% palladium on charcoal is hydrogenated at 60 and an initial pressure of 3 at. for about 40 minutes. It is filtered, the filtrate evaporated and the residue recrystallized from diethyl ether, to yield the a-(Z-carboxylbenzyl)-phenylacetonitrile melting at 121.5 to 124.

To the solution of 21.5 g. thereof in 500 ml. methylene chloride, 21 g. phosphorous pentachloride are added portionwide during 20 minutes while swirling. After standing for 1% hours at room temperature, it is chilled, washed with water, 2% aqueous sodium hydroxide and water, dried, filtered, evaporated and the residue triturated with petroleum ether, to yield the a-(2-chlorocarbonylbenzyl)- phenylacetonitrile melting at -87".

To the solution of 2.3 g. -carbamoyl-10,1l-dihydro- SH-dibenzo[a,d]cycloheptene in 200 ml. tetrahydrofuran, 45 ml. of a 1 molar solution of boron hydride in tetraa hydrofuran are added and the mixture refluxed for 3 hours. After cooling, 200 ml. water and ml, 'concen, trated hydrochloric" acid are added and the mixture concentrate'd to about half of its original volume. The concentrate. is washed with diethyl ether, made basic with aqueous sodium .hydroxide and extracted with diethyl ether. The extract is washed with" water, dried and evap-. orated, The residueis taken up in ethanol, the solution acidified with ethanolic hydrochloric acid and the precipitate formed recrystallized from ethanol, to yield the 10- aminomethyl -10,1l-dihydro 5H dibenzo[a-,d] cycloheptene hydrochloride of the formula melting at 229-230. The starting material is prepared as follows: The mixture of g'. of 5-oxo-10-eyano-10,1l-dihydro-SHediben? zo[a,d]cycloheptene, 200 ml. glacial acetic acid and 300' ml. concentrated hydrochloric acid is refluxed for 3 hours and concentrated in vacuo. The concentrate is poured into ice water, the precipitate formed filtered off and taken up in 5% aqueous sodium bicarbonate. The solution is washed with diethyl ether, acidified with hydrochloric acid and extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from diethyl ether, to yield the 5-oxo-10- carboxy-l0,11-dihydro 5H diben'zo[a,d]-cycloheptene melting at 144-145 The mixture of 15 g. thereof, 200 ml. glacialacetic acid and ,5 g. 10% palladium on charcoal'is hydrogenated atj70 underan initial pressure of 3. at. until the hydrogenuptake ceases. It is filtered, the filtrate evaporated in mm, the residuetriturated with petroleumether and recrystallized from'petroleum ether-diethyl ether, to yield the 10-carb0xy-10,1 l-dihydro SSH 'dibenzoic [a ,d] cyclo heptene melting at 120l21" 'jThemixture of .6 g. thereof, 50 ml. thionyl chloride and a drop of dimethylformamide is refluxed for V2 hour,' evaporated irtvacuo, the residue taken up in benzene and again evaporated in vacuo; to yield the corresponding acid chloride It is taken up in 100 ml. concentrated aqueous ammonia,"the mixtures stirred for 1 hour, filtered, the residue washed with water; dried and'recrystallizedjfrom methanol, to I yield' the 10-"carb'am0yl-10,1l-dihydroJl-L. dibenzo[a,d].cycloheptene melting at 188-189".

EXAMPLE -3 7;.- "To' the solution of 28 g. 10-methylcarbamoyl-10,11: dihydro-5H-dibenzo[a,d]cycloheptene in 100 ml. tetrahy droftiran, 50 ml. of a 1 molar solution of boron hydride in tetrahydroftiran are added and the mixture refiuxed'for' 3' /2' hoursjAfter cooling, 50 ml. water, =50 m1. acetic acid and 10 ml. concentrated hydrochloric acid are added, the mixture refluxed for one hour, allowed to stand overnight and evaporated in vacuo. The residue is taken up 8. in water, the mixture filtered,'the" filtrate made basic with aqueous sodium hydroxide, extracted with diethyl ether, the extract washed with water, dried,'filtered and evap orated. 'The'residue is taken up .in ethanol, the solution acidified'with ethanolic hydrochloric acid, the precipitate formed filtered off and recrystallized from ethanol, to yield the 10-methylaminomethyl-10,1'1-dihydro-5H-dibenzo[a,d]cycloheptene hydrochlorideof the formula CHENHQE'HCI melting at24 5' -246" with decomposition. 3

The starting material'is pteparedsfolldws; To the solution of 3 g. 10-chlorocarbonyl-l0,-1I dihydrO SH-di benzo[a,d]cyeloheptene in the minimum amount of diethyl ether, 15 ml. 40% aqueous'methyl'amine are added dropwise and the mixture stirred for one hour. -It is diluted with IOO ml. water, filtered, the'residue washed with water, driedand recrystallized from ethanol, to yield the 10 methyl'carbamoyl-10,1'1-dihydro-5H-dibenzo[a,d]

. cycloheptene melting at melting at s'ajstqs s jf aterial, prepar j as renews: ref- 4o ml anhydrous dirnethyla'fnine,jf3.5 g; ,1 O-ehloroca'rbonylf 1 ,1 hYFliQ-5H d iben'zoI a,d]cy'cloheptene1in' themini trahydrg furanjjare" added while stirring allowedto'stand atfr'o'om temperature" p thylainineflisevaporated. Theresidue is triturated .Wl thf r' "rid tliethyl ether-iand;reerystal uiea fr'onimethanol, tojyleld the 1tj-dim'ethyl'earbamoyl- XA L JJ .1

. T h, s lut b 1, 5It."l -sltst l rbamoy ;!1- din ar'dsHhiben ot d]cycl ohepte'ne, in too m1, ;te trshydreruramfmjm l; (Slat-"solution ot bor'o'nihydriedinnt 'e traliydr uran a: diam! the refluxe d tor 311/1. hours, f cb0l ng,. mtgwa egme added dropwise andthe' mixth re concentrate'd' to about 5 m 11 .m t nentrae o mti a r. sem a jc' c d and 10 -ml. concentrated hydrochloric acid are added, 'the iXt meI fl m torlfl hQ fi l Wd o, S and, piie nis t a d, evaporatedgznvg pITheirefsidue is taken up in water, the mixture filtered, thej fi lt'ratle magma-sic aqueou' wd um hydr e. nd e tratsd i PhYl, li Th extract is'shalten with"5 hydrochloric acid, the aqueous layer made :basic with sodium-hydroxide" and again "ex tracted fwith diethyl' e'therQ Th'e extract" is washes'witu water, dried andevaporatedi The'r'esidue "is taken upiin ethanol, ere solution acidifiedwith ethanolic hydro chloric acid and'th'elprecipitateformed recrystallized from ethanol,- to yield the IO-diethylainindmethyl-10,"1-l-di- 9 hydro-5H-dibenzo[a,d]cycloheptene hydrochloride of the formula melting at 170-172".

The starting material is prepared according to the method described in the previous examples; it shows in the LR. spectrum a strong band at 6.13 Substituting it by:

(a) 2.7 g. l-pyrrolidinocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, M.P. 169-170 (ethanol); (b) 3 g. 10-piperidinocarbonyl-10,1l-dihydro-SH-dibenzo [a,d1cycloheptene, M.P. 157-158 (diethyl ether);

(c) 3.4 g. 10-hexamethyleneiminocarbonyl-10,11-dihydro- 5H-dibenzo[a,d]cycloheptene, M.P. 144-146 (ethanoldiethyl ether);

(d) 8.0 g. -(4-benzylpiperazinocarbonyl)-10,ll-dihydro-SH-dibenzo [a,d] cycloheptene, M.P. 241-243 (ethanol);

(e) 4.6 g. 10-(3-dimethylaminopropylcarbamoyl)-10,1l-

dihydro-5H-dibenz0[a,d] cycloheptene, M.P. 108-1 10 ethanol);

(f) 4.5 g. 10-(N-methyl-2-dimethylaminoethylcarbamoyl) 10, 1 l-dihydro-SH-dibenzo [a,d] cycloheptene, M.P. hydrochloride hemihydrate, M.P. 190-192" (ethanol);

(g) 4.2 g. 10-(4-phenylpiperazinocarbonyl)-10,ll-dihydro-SH-dibenzo [a,d] cycloheptene, M.P. 179-18 1 (ethanol);

(h) 4.7 g. 10-(4-phenylpiperidinocarbonyl)-10,1l-dihydro-SH-dibenzo[a,dJcycloheptene, M.P. 162164 (ethanol); or

(i) 6.0 g. 10-heptamethyleneiminocarbonyl-10,1l-dihydro- SH-dibenzo[a,d]cycloheptene, M.P. 119-120 (ethanol),

and following the procedure shown in the beginning, the following compounds are obtained:

(a) 10-pyrrolidinomethyll0, 1 l-dihydro-S'H-dibenzo [a,d]cycloheptene hydrochloride, M .P. 23 5-237 (ethanol-diethyl ether);

(b) 10-piperidinomethyl-10,l1-dihydro-5H-dibenzo[a,d]

cycloheptene hydrochloride, M.P. 200-201 (ethanoldiethyl ether);

(0) 10-hexamethyleneiminomethyl-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene hydrochloride, M.P. 194- 195 (ethanol-diethyl ether);

(d) l0(4-benzylpiperazinomethyl)-10',1l-dihydro-SH- dibenzo [a,d] cycloheptene dihydrochloride hemihydrate, M.'P. 237-239 (ethanol);

(e) 10-(3-dimethylaminopropylaminomethyl)-10,1l-

dihydro-5I-I-dibenzo[a,d] cycloheptene dihydrochloride, M.P. 237-239" (ethanol);

(f) 10-(N methyl-Z-dimethylaminoethylaminomethyl)- 10,1 1-dihydr0-5'H-dibenzo[a,d] cycloheptene, M.P. dipicrate, M.P. 213-215 (ethanol);

(g) 10-(4-phenylpiperazinomethyl)-10,1 l-dihydro-SH-dibenzo [a,d] cycloheptene dihydrochloride monohydrate, M.P. 225-228 (methanol-diethyl ether);

(h) 10-(4-phenylpiperidinomethyl)-10,1 l-dihydro-SH-di- 'benzo[a,d] cycloheptene hydrochloride, M.P. 252-255 (ethanol); and

(i) lO-heptamethyleneiminomethyl-l0,1 I-dihydro SH-dibenzo[a,d]cycloheptene, M.P. picrate 208 210 (ethanol).

EMMPLE 6 The mixture of 3.5 g. 5-oxo-IO-dimethylcarbamoyl-lO, 1l-dihydro-5H-dibenzo[a,d]cycloheptene, 400 ml. diethyl ether and 7 g. lithium aluminum hydride is refluxed for 7 hours while stirring. After cooling, 35 ml. water are added dropwise during one hour, the mixture filtered, the filtrate dried and evaporated. The residue is taken up in the minimum amount of diethyl ether and, during several days, crystals separate, which are recrystallized from diethyl ether, to yield the higher melting isomer of the 5g-hydroxy- 10 dirnethylaminomethyl-l0,11-dihydro-5H-dibenz0[a,d] cycloheptene of the formula CHa-N (CH1):

melting at 169-171 The combined mother liquors are allowed to stand in the refrigerator and the precipitate formed recrystallized from diethyl ether, to yield the other, lower melting isomer of the above formula, melting at 110-111 /2".

The starting material is prepared as follows: The mixture of 7.5 g. 5-oxo-10-carboxy-10,11-dihydro-5H-dibenzo- [a,d]cycloheptene, 100 ml. thionyl chloride and one drop dimethylformamide is refluxed for /2 hour and evaporated in vacuo at 100. The residue is taken up in benzene, the mixture evaporated and the residue recrystallized from diethyl ether, to yield the 5-oxo-10-chlorocarbonyl-l0,11- dihydro 5H dibenzo[a,d]cycloheptene melting at 108-1 10 4 g. thereof are added portionwise to 45 ml. anhydrous dimethylamine and the mixture allowed to evaporate overnight. The residue is taken up in water, the mixture extracted with diethyl ether, the extract washed with water, dried and evaporated, to yield the S-oxo-IO-dimethylcarbamoyl-l0,l1-dihydro 5H dibenzo[a,d]cycloheptene, which is used as such without further purification.

In the analogous manner, other 5-oxo-10-amides are prepared using an excess of the following reactants:

(a) concentrated aqueous ammonia- 10-amide, M.P.

161-162" (ethanol-diethyl ether) (b) saturated methylamine benzene- 10-methylamide,

M.P. 212-213 (methanol) (c) anhydrous diethyla-mine-xIO-diethylamide, M.P.

86 (diethyl ether) (d) morpholine 10-morpholide, M.P. 147-148 (methanol-diethyl ether) (e) l-methyl-piperazino10-(4-methylpiperazide), M.P.

128-129 (methanol-diethyl ether) Hydrogenating the above starting materials in glacial acetic acid over palladium on charcoal at about 60-70", the corresponding 5-desoxo-10-amides are obtained, which are identical with those described in Examples 2-5, 7 and 8.

EXAMPLE 7 To the solution of 3.7 g. 10-(4-methylpiperazinocarbonyl 10,11 dihydro-SH-dibenzo[a,d]cycloheptene in ml. tetrahydrofuran, 50 m1. of a 1 molar solution of boron hydride in tetrahydrofuran are added and the mixture refluxed for 3 /2 hours. After cooling 100 ml. water, 100 ml. concentrated hydrochloric acid and 200 ml. glacial acetic acid are added while stirring, the mixture refluxed for 3 hours and allowed to stand for 3 days at room temperature. It is concentrated to about 200 ml., the concentrate combined with 200 ml. acetic acid and refluxed for 2 hours. It is evaporated in vacuo, the residue taken up in water, the solution filtered and the filtrate made basic with 10% aqueous sodium hydroxide. It is extracted with diethyl ether, the extract washed with Water, dried, evaporated and the residue recrystallized from diethyl ether, to yield the 10-(4-methylpiperazino- 1'1 methyl) 510,11- dihydro 5H-dibenzo[a,d]cycloheptene hemihydrate of theformula a Y CH -N 1 N-om 'IIZHQO melting at s1-s2. 'Its dihydrochloride sesquihydrate is prepared from ethanolic hydrogen chloride and melts, after drying at 80 in vacuo, at 242-244.

The starting material is prepared as follows: To the solution of 10-chlorocarbonyl-10,ll-dihydro-SH-dibenzo [a,d]cyclo-heptene in the minimum amount of diethyl ether, 12 ml. l-methyl-piperazine are added portionwise while stirring. After one hour, 5 ml. water are added and the ether evaporated at the steam cone. The sus pension is filtered, the residue washed with water and recrystallized from ethanol, to yield the- 10-(4-methylpiperazino-carbonyl) 10,11 dihydro-5H-dibenzo[a,d] cycloheptene melting at 163164. Y. a

,, EXAMPLE 8 I I a v The mixture of 6'g..of 5oxo-10-(4-methylpiperazinocarbonyl) 10,1l-dihydro-5H-dibenzo[a,d] cycloheptene, 300'ml .'tetrahydrofuran and 15 g. lithium aluminum hy-. dride isrefluxed for 3 hours while stirring. After cooling, it is diluted with 400 ml. diethyl ether and 65ml. water are added during 1 hour. It is filtered, the filtrate dried, evaporated and the residue recrystallized from methanol, to yield the S-hydroxy-10-(4-methylpiperazinomethyl) 10,1l-dihydro-SH-dibenzo[a,d]cycloheptene of the formula 1 7, I

urn-N N-CH;

melting at 235-2379. v EXAMPLE-9' To the solution of 3 g. 10-[4-(2 hydroxyethyl)=pipera tene and'100 ml. tetrahydrofuran,501ml.of .lfmolar boron hydride in tetrahydrofuran are added whilej'stir 56 ring, and the mixture refluxed "for 3 /2 hours. It iS'OOlCd and ice is added until the-hydrogen'evolution' ceases. After the addition of -20 ml. water and ZQ-mlgacetic acid, .the mixture is evaporated at thesteam 0036,41); residue taken up in 80 ml. .water, ml. acetieacid and: 20 ml. concentrated hydrochloric acid, the mixture re; fluxed for /2 hour and evaporated in vacuo. The residue is taken up in water, thesolution filtered, the filtrate made basic with 10% aqueous sodium hydroxide and extracted wi,th diethyl ether. {The extract iswashed with water,;.-dried, evaporated and .the residue taken up. in ethanolic hydrogen chloride. The precipitate formed is filtered off, washed with diethyl ether and recrystallized from ethanol-acetone, to. .yield the; 1,0-[4-(2-hydroxyeth-" yl).-piperazinomethyl]-10,1 l -dihydro, 5H,---.d,ibenzo[a,d] cycloheptenedihydrochloride. of, theformula;

v CH -N l. Na-olm-ou-znoi at 245250 with decomposition (methanol).

The starting material is prepared as follows: To themixture of 6.5 g. 10-chlorocarbonyl-10,1l-dihydro-SH dibenzo[a,d]cycloheptene in 150 ml. diethyl ether, 12 ml. l-(2-hydroxyetl1yl)-plperazine are added dropwise while stirring and the mixture allowed to stand for 1 hour at room temperature. It is evaporated on the steam bath, the residue poured onto ice water, the supernatant phase decanted off and the residue washed with water. It is taken up in 25 ml. ethanol, the solution diluted with water until it becomes cloudy and allowed to stand in the refrigerator. The precipitate formed is filtered off, washed with water and recrystallized from ethanol-di-i ethyl ether, to yield the 10-[4-(2-hydroxyethyl)-pipera zinocarbonyl-10,l1-dihydro 5H dibenzo[a,d]cycloheptene melting at 116-118. I

EXAMPLE 10 To-the solution of 2.5 g. IO-morpholinocarbonyl-IO, l'l-dihydro-SH-dibenzo[a,d]cycloheptene in 100 ml. tetrahydrofuran, 50 ml. of a 1 molar solution of boron hydride in tetrahydrofuran are added and the mixture refluxed for 3 /2 hours. After cooling, 50 ml. water are added dropwise, followed by 5 ml. acetic acid and the mixture concentrated to about 25 ml. The concentrate is combined with 50 ml. water, 50 ml. acetic acid and 10 ml. concentrated hydrochloric acid, refluxed for 1 hour, allowed to stand overnight and evaporated in vacuo. The residue is taken up in water, the solution filtered, the filtrate made basic with 10% aqueous sodium hydroxide and extracted with diethyl ether. The extract is washed with water, dried, evaporated, the residue taken up in ethanolic hydrogen chloride, the precipitate taken up in water, the solution made basic and extracted again with diethyl ether. The extract is washed with water, dried and evaporated, to yield the 10-morpholinomethyl-10,ll-dihydro-SH-dibenzo [a,d]cycloheptene of the formula melting t 128-1309.

EXAMPLE 11 To the solution of 2.2 g. l0-(2-dimethylaminoethylcarbamoyl) -10,11 dihydro-SH-dibenzo[a,d]cycloheptene in .50 ml. tetrahydrofuran, 75 ml. of a 1 molar solution of boron'hydridein tetrahydrofuran are added and the mixture'refluxed for 3 hours. After cooling, 20 ml. water, 10 ml. acetic acid and 5 ml. concentrated hydrochloric acid are added andthe'mixture concentrated to about 50 nilnHereupon ml. water, 30 ml. acetic acid and 30. ml. concentrated hydrochloric acid are added, the mixturerefluxed for 4 hours and evaporated in vacuo. The residue'is taken up in water, the mixture filtered, the filtrate made basic with 2 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is washed with water, "driedand evaporated, to yield the oily 10- (Ldimethylarninoethylaminomethyl) 10,11 dihydror SH-dibenzo[a,d]cycloheptene of the formula I om-Nn-cm-oni-mcm).

13 EXAMPLE 12 To the solution of 3.4 g. 7-methyl-10-(4-methylpiperazinocarbonyl) 10,11 dihydro-H-dibenzo[a,d]cycloheptene in 100 ml. tetrahydrofurafi, 50 ml. of a 1 molar solution of boron hydride in tetrahydrofuran are added, 5 and the mixture refluxed for 3 /2 hours. After cooling, 50 ml. water and'30 ml. concentrated hydrochloric acid are added and the mixture concentrated on the steam cone. The concentrate is diluted with 70 ml. concentrated hydrochloric acid and 100 ml. acetic acid, refluxed for 5 /2 hours and evaporated in vacuo. The residue is taken up in water, the solution filtered, the filtrate made basic with 2 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is washed with water, dried, evapw rated and the residue recrystallized from diethyl ether, to yield the 7-methyl-10-(4-methylpiperazinomethyl)- 10,11-dihydro-5H-dibenzo[a,d]cycloheptene of the formula CHI-N NCH;

melting at 117-1185.

The starting material is prepared analogous to the method described in Examples 1, 2 and 9. The respective intermediates have the following melting points (if not otherwise stated, the same solvent for recrystallization is used):

111 (ethanol); (b 5.7 g. 7-methyl- 1 O-dimethylcar-bamoyl- 10, 1 l-dihydro- 5=H-dibenzo[a,d]cycloheptene; or (c) 5.8 g. 7-methyl-IO-diethylcarbamoyl-10,1l-dihydro- 5H-dibenzo[a,d]cycloheptene, and following the procedure shown in the beginning, th following compounds are obtained:

(a) 7-methyl-10-hexamethyleneiminomethyl-10, 1 1- dihydro-5H-dibenzo[a,d]cycloheptene hydrochloride, M.P. l83186 (ethanol-diethyl ether);

(b) 7-methyl-10dimethylaminomethyl-10, 1 l-dihydro- 5H-dibenzo[a,d]cycloheptene hydrochloride, M.P. 21l-2l3 (ethanol-diethyl ether); and

(c) 7-methyl-10-diethylaminomethyl-IO,1 l-dihydro- SH-dibenzo[a,d]cycloheptene hydrochloride, M.P. 164166 (ethanol-diethyl ether).

EXAMPLE 13 The solution of 2 g. 5,10-(iminomethano)-10,1l-dihydro-5H-dibenzo[a,d]cycloheptene hydrochloride in 100 ml. of ethanol is hydrogenated over 0.5 g. palladium on charcoal at 80 and 3 at. After the absorption of the theoretical amount of hydrogen, the mixture is filtered, the filtrate evaporated and the residue recrystallized from ethanol, to yield the 10-aminomethyl-10,1l-dihydro-SI-I- dibenzo[a,d]cycloheptene hydrochloride melting at 229- 230; it is identical with that obtained according to Example 2.

The starting material is prepared as follows: To the solution of 20.7 g. 5-oxo-10-carboxy-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene in 300 ml. methanol, 30 g. sodium borohydride are added portionwise while stirring, the mixture heatedon the steam cone for /2 hour and slowly evaporated. The residue is taken up in 300 ml. water, the mixture filtered and the filtrate acidified with hydrochloric acid. The precipitate formed is filtered off, washed with water, dried and recrystallized from diethyl ether, to yield the cyclic lactone of the S-hydroxy-lO-carboxy-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene melting at 152-153.

5.25 g. thereof are added portionwise to the filtered mixture, prepared from 35 g. hydroxylamine hydrochloride, 20 ml. water, 120 ml. ethylene glycol and 14 g. sodium hydroxide at 0. The mixture is refluxed for 13 hours and allowed to stand at the steam cone for 4 days. It is diluted with water, filtered, the residue washed with water and recrystallized from diethyl ether, to yield the corresponding cyclic hydroxarnic acid lactone of the formula $0 NOH melting at 237-239.

19.5 g. thereof are hydrogenated in 1.8 liters ethanol over 10 g. Raney nickel at 70 and 3.4 at. for minutes and filtered hot. The catalyst is washed with hot ethanol, the filtrate evaporated and the residue recrystallized from ethanol-diethyl ether, to yield the corresponding cyclic lactam melting at 226-228".

The mixture of 5.6 g. thereof, 12 g. lithium aluminum hydride and 500 ml. tetrahydrofuran is refluxed for 5% hours while stirring and allowed to stand overnight at room temperature. It is diluted with diethyl ether, 60 ml. water are added dropwise during 1 hour while stirring and filtered. The filtrate is dried, evaporated, the residue taken up -'in ethanol, the solution acidified with ethanolic hydrogen chloride and the precipitate recrystallized from ethanol-diethyl ether, to yield the 5,10-(iminomethano)- 10,11'-"-dihydro 5H-dibenzo[a,d] cycloheptene hydrochloride of the formula NH \i/ melting at 272-274 with decomposition.

I EXAMPLE 14 2 g. N-methyl-5,10-(iminomethano)-10,1 l-dihydro-SH- dibenzo[a,d] cycloheptene hydrochloride are hydrogenated in ml. ethanol over 0.5 g. palladium on charcoal at 3.4 at. and 80". After 2 hours, the mixture is filtered hot, the filtrate evaporated and the residue recrystallized from ethanol, to yield the 10-methylaminomethyl-10,1l-dihydro-SH-dibenzo[a,dJcycloheptene hydrochloride melting at 245-246 with decomposition; it is identical with that obtained according to Example 3.

The starting material is prepared as follows: To the solution of 5.5 g. of the cyclic lactam of the 5-amino-10- carboxy 10,11 dihydro-SH-dibenzo [a,d]cycloheptene in 400 ml. toluene, 1.15 g. 56% sodium hydride in mineral oil are added and the mixture stirred on the steam cone until the hydrogen evolution ceases. Hereupon 50 ml. methyl iodide are added and the mixture refluxed for 3% hours while stirring. After cooling, it is diluted with di- ..Preparation of 10,000 tablets each containing 100.0 mg. of the active ingredient: a

Formula; I G.

10 (4 methylpiperazinomethyl)-l;11-

dihydro 5H dibenzo[a,d] cycloheptene dihydrochloride sesquihydrate 1,000.00 Lactose j.. 2,535.00 Corn starch 125.00 Polyethylene glycol 6,000 150.00 Talcum powder 150.00 Magnesium stearate 40.00

Purified water, q.s.

Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the (4-methylpiperazinomethyl) 10,11 dihydro SH-dibenzo[a,d]cycloheptene dihydrochloride sesquihydrate, lactose, talcum,'magnesium stearate and half of thestarch are mixed in a suitable mixer. The other half of the starch is suspended i n 65 ml. water and the suspension added to the boiling solution of the polyethylene glycol in 260 ml. water; The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35 broken on'a screen with 1.2 mm. openings and compressed into tablets using concaye punches with 10.3 mm. diameter, uppers bisected.

EXAMPLE l6 (dHa-f' melting at 285-287 with decomposition. l dllip e The starting material is prepared as descri H previous examples. It melts at 131-133? (ethanol):

' EXAMPLE 17 To "the solution of 3.7 g. 10-cyclopropylcarbamoyl lQ 11 dihydro-5H-dibenzo[a,d]cycloheptene, 6; g. lithium aluminum hydride are added portionwise andth'e mixture refluxed for 5 hours while stirring. After cooling;2 5 ml. water are added dropwise, the mixture filtered, the filtrate dried and evaporated, to yield the 10-cyclopropylamino- HCl 1 6 methyl-10, 1 l-dihydro 5H-diben'zo [a,d] cycloheptene of the formula p a -me 1 showing in the LR. spectrum a strong band at The-starting material is prepared as shown in thepre f' vious examples. It melts-at 202-20450 (diethylether).

A .-,EXAMPLE 18,

1 To'the "mixture I 200 mlj-tetr'ahydrofu'ran', the solutiono f 5.5 g.' -10-(N-:' methyl-N-benzylcarbamoyl) 10,11-dihydro 5H-dibenzo [a,d]cycloheptene' in 200 ml. tetrahydrofuran is slowly added while stirring and the mixture refluxed for 4 hours. After standingoyernight, 25 ml. -water are added during 1 hour, the mixture filtered, the filtrate dried, evaporated and the residue recrystallized from diethyl ether, to yield the 10 (N-methyl-N-benzylaminomethyl) 10,11-dihydro-SH-dibenzo [a,d] cycloheptene of the formula melting at 188-190. l

The corresponding hydrochloride melts at;202,-205.' (ethanol) with decomposition and the starting material at 122- 1235 (diethylethenpetroleum ether);

. t Q..,, XA 9 Y To the solution of 5.5 g. l0-methyl-10-(4 methylpiperazinocarbonyl) 10,11 dihydro 5H-dibenzo[a,d] cycloheptene in ml. tetrahydrofuran areadded 50 ml. of a 1 molar solution-of boron hydridein tetrahydr ofuran and the; mixture refluxed for 4 hours. After cooling, .50 ml. water and 30ml. concentrated hydrochlorieacid'are added and the"mixture-concentratedtotabout- 8 0 ml. Hereupon 70 :ml. concentratedv hydrochloric. acid and vml. glacial acetic acid are added, the mixture refluxed ior 6 hours and evaporated ir vrzcx o. The residue is taken up in water, the mixture filtered, the filtratemade basic' with potassium icarbonate-andextracted :with diethyl ether. The extract is: washed, with waterudried and evaporated, to yield the oily IQ-methyl-IO-(4-methylpiperazinomethyl)- 10,1 1#dihydrc5H*dibenzo[a,d] cycl'oheptene of the for.- mula i on, car-7N Neon,

, hours; then heated ona st'ea m con e. Upon cooling, the

mixture is'treated with ice and water and extractedwith of 5' g. lithiumaluminum-hydrideand 17 diethyl ether. The extract is washed with water, dried and evaporated to give the crude S-oXo-IO-methyl-IO-cyano- 10,1 l-dihydro-SH-dibenzo [a,d] cycloheptene.

The solution of 15 g. thereof in 150 ml. glacial acetic acid and 200 ml. concentrated hydrochloric acid is refluxed for 3% hours and evaporated in vacuo. The concentrate is diluted with ice and water and extracted with diethyl ether. The extract is washed with water, dried and evaporated. The residue is made crystalline with diethyl ether. Recrystallization from diethyl ether affords the 5-oxo-10- methyl 10-carboxy-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene, melting at 142-144".

16.5 g. thereof is hydrogenated in 150 ml. glacial acetic acid with 6 g. 10% palladium on charcoal under 3 atm. hydrogen at 70 for 3 hours. The catalyst is filtered OE and the filtrate evaporated in vacuo. The residue is crystallized from petroleum ether, yielding the IO-methyl-IO- carboxy-10,11-dihydro 5H dibenzo[a,d]cycloheptene, M.P. 169-171.

The mixture of 5 g. thereof, 50 ml. thionyl chloride and 2-3 drops of dimethyl formamide is refluxed for 1/2 hour and evaporated in vacuo. The residue is taken up in benzene and evaporated once more in vacuo. The crude acid chloride obtained is dissolved in 100 m1. diethyl ether and treated with 10 ml. N-methylpiperazine, added portionwise. The mixture is allowed to stand for 1 hour and then diluted with water. The layers are separated and the aqueous layer extracted with diethyl ether. The combined ether layers are washed with water, dried and evaporated. The residue is recrystallized from diethyl ether-petroleum ether, to give the 10-methyl-10-(4-methylpiperazinocarbony1)-10,1l-dihydro 5H dibenzo[a,d]cycloheptene, M.=P. 124-126.

In an analogous manner, the following amides are prepared:

(a) Ill-methyl-10-hexamethyleneiminocarbonyl-10,1l-dihydro-SH-dibenzo [a,d] cycloheptene, M .P. 116-118 (ethanol);

(b) 10-methyl-lO-diethylcarbamoyl-10,l l-dihydro-SH-di- 'benzo[a,d]cycloheptene, M.P. 84-87 (diethyl ether);

() lO-methyl-IO-piperidinocarbonyl-l0,1 l-dihydro-SH- dibenzo[a,d]cycloheptene, M.P. 116-l19 (diethyl ether);

(d) IO-methyl-IO-dimethylcarbamyl-10,1 l-dihydro-SH- dibenzo[a,d]cycloheptene, M.P. 125-l27 (ethanol); and

(e) 10-methyl-IO-methylcarbamoyl-IO,1 1-dihydro-5H-dibenzo[a,d]cycloheptene, M.P. 190-192 (ethanol),

which on reduction with borane as described above aiford the following compounds:

(a) 10-methyl-10-hexamethyleneiminomethyl-l0,1 l-dihydro-SH-dibenzo[a,d]cycloheptene hydrochloride, M.P. 243-246 with decomposition (ethanol);

(b) lO-methyl-lO-diethylaminomethyl-IO,1l-dihydro- SH-dibenzo[a,d]cycloheptene hydrochloride, M.P. 262- 263 with decomposition (ethanol);

(0) lO-methyl-IO-piperidinomethyl-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene hydrochloride, M.P. 277-280 with decomposition (ethanol);

(d) 10-methyl-IO-dimethylaminomethyl-l0,1 1-dihydro H-dibenzo[a,d]cycloheptene hydrochloride, M.P. 276- 278 with decomposition (ethanol); and

(e) IO-methyl--methylaminomethyl-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene hydrochloride, MJP. 282- 284 with decomposition (ethanol).

EXAMPLE 2.0 g. 10-p-toluenesulfonyloxymethyl-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene are heated with 10 ml. piperidine on a steam cone for 2 hours. The mixture is evaporated in vacuo, diluted with water and extracted with diethyl ether. The extract is washed with water, dried and evaporated. The residue is taken up in ether and treated 18 withethanolic, hydrogen chloride, to afford the IO-piperidinomethyl-l0,1l-dihydro-SH dibenzo[a,d]cycloheptene hydrochloride, melting at 200-201 (ethanol-diethyl ether); it is identical with that obtained according to Example 5 (b).

The starting material is prepared as follows: To the solution of 20 g. 10-carboxy-10,ll-dihydro-SH-dibenzo- [a,d]cycloheptene in ml. tetrahydrofuran is added dropwise to 150 ml. of a 1 molar solution of borane in tetrahydrofuran. The resulting mixture is refluxed for 5 hours, cooled, treated with water, made basic with 10% aqueous sodium hydroxide and further treated with 100 ml. 30% aqueous hydrogen peroxide. The mixture is stirred for 2 hours and the tetrahydrofuran distilled off. The aqueous mixture is extracted with diethyl ether and the extract washed with water, dried and evaporated, to give the 10-hydroxymethyl-10,11-dihydro-5H-dibenzo[a, d] cycloheptene.

To the solution of 8.6 g. thereof in 75 ml. pyridine is added 15.3 g. p-toluenesulfonyl chloride at 0". The mixture is allowed to stand for 3 days and then treated with 1 liter of ice and water. The mixture is extracted with diethyl ether and the extract is washed successively with water, 10% hydrochloric acid and water, dried and evaporated, to afford the 10-p-toluenesulfonyloxymethyl-10, 1l-dihydro-SH-dibenzo[a,d]cycloheptene, M.P. 124-126 (diethyl ether).

EXAMPLE 21 1.4 g. 10-piperidinomethyl-SH-dibenzo[a,d]cycloheptene is hydrogenated in ml. glacial acetic acid with 0.5 g. 10% palladium on charcoal under about 3 atm. of hydrogen at 70 for 7 hours. The catalyst is filtered off and the filtrate evaporated in vacuo. The residue is taken up in water, made basic with 10% aqueous sodium hydroxide and extracted with diethyl ether. The extract is washed with water and extracted in turn with 6 N hydrochloric acid. The organic layer is discarded and the aqueous acid extract is made basic with 10% aqueous sodium hydroxide and then extracted with diethyl ether. The extract is washed, dried and evaporated. The residue is taken up in diethyl ether and treated with ethanolic hydrogen chloride. The salt formed is collected on, a vfilter and recrystallized from ethanol-diethyl ether, to give the 10-1. piperidinomethyl-10,1l-dihydro 5H dibenzo[a,d] cycle-I heptene hydrochloride, melting at 200-201; it is.identical, with that obtained according to EXamples'S. (b) and 20; L

EXAMPLE .2 v

To the solution of 5.2 g. 10-(4-carboethoxy-piperazino carbonyl)-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene in 100 ml. tetrahydrofuran are added, 65 ml.- of a '1' molar solution of boron hydride in tetrahydrofuran and the mixture refluxed for 4 hours. After cooling, 50"ml.--water,-' 200 ml. glacial acetic acid and ml. concentrated bydrochloric acid are added, and themixture is concentrated to a volume of about 400 ml. The mixture is then refluxed for 7 hours and evaporated in vacuo. The residue is taken up in water, filtered and the filtrate madebasic with potassium carbonate. The basic mixture is extracted with diethyl ether and the extract washed, driedj" and evaporated, to yield the 10-piperazinomethyl-10,ll-dihydro-5H-dibenzo [a,d]cycloheptene of the formula om-N a ture of 4 g. 10 carboxy-l0,11-dihydro-5H-dibenzo[a,d]

dimethylformamide is refluxed for /6 hour and evaporated in vacuo. The residue is taken up in benzene and evaporated once more. The crude acid chloride obtained is dissolved in 100 ml. diethyl ether and treated with 12 ml. N-carboethoxypiperazine, added in portions. The mixture is allowed to stand for 1 hour and then diluted with water. The layers are separated and the aqueous layer extracted with diethyl ether. The combined ether layers are washed with water, dried and evaporated. The solid residue is recrystallized from diethyl ether, to afford the 10-(4-carboethoxypiperazinocarbonyl) 10,11-dihydro-5H-dibenzo [a,d]cycloheptene, melting at 119121.

EXAMPLE 23 3.1 g. 10 (4-benzylpiperazinomethyl)-l0,1l-dihydro 5H-dibenzo[a,d]cycloheptene dihydrochloride, described in Example 5(d), is dissolved in 150 ml. ethanol and treated with 3 g. 10% palladium on carbon under about 3 atm. of hydrogen at 5560 for 2 hours. After cooling, the catalyst is filtered off and the filtrate evaporated, to give the 10-piperazinomethyl-10,1l-dihydro-SH-dibenz0[a,d]cycloheptene dihydrochloride monohydrate, M.P. 262-264 (ethanol); it has the same structural formula as that shown in Example 22.

What is claimed is: 1. A compound having the formula R. GHQ-Ami R1 RI wherein each of R and R is hydrogen, methyl, methoxy, chloro, trifiuoromethyl, nitro or amino, R is hydrogen 20 or methyl, .Am is pyrrolidino, piperidino, 4-phenyl-piperidino, hexamethyleneimino, piperazino, morpholino or 4- (methyl, ethyl or 2-hydroxyethyl)-piperazino and X represents two hydrogen atoms, or therapeutically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1 and being the 10- piperidinomethyl 10,11 dihydro-SH-dibenzo [a,d]cycloheptene or a therapeutically useful acid addition salt thereof.

3. A compound as claimed in claim 1 and being the 10- morpholinomethyl-IO, 1 l-dihydro-SH-dibenzo [a,d] cycloheptene or a therapeutically useful acid addition salt thereof.

4. A compound as claimed in claim 1 and being the 10- (4 methylpiperazinomethyl) 10,11-dihydro-5H-dibenzo [a,d]cycloheptene or a therapeutically useful acid addition salt thereof.

5. A compound as claimed in claim 1 and being the 10- (4 phenylpiperidinomethyl) 10,11 dihydro-SH-dibenzo [a,d]cycloheptene or a. therapeutically useful acid addition salt.

References Cited UNITED STATES PATENTS Fouche 260240 NICHOLAS S. RIZZO, Primary Examiner J. TOVAR, Assistant Examiner US. Cl. X.R.

260239 B, 247.5 R, 247.7 C, 247.7 H, 268 TR, 268 C 293.62, 326.5 C, 326.81; 424248 

